Quinolines, trifluoromethyl

Reduction. Quinoline may be reduced rather selectively, depending on the reaction conditions. Raney nickel at 70—100°C and 6—7 MPa (60—70 atm) results in a 70% yield of 1,2,3,4-tetrahydroquinoline (32). Temperatures of 210—270°C produce only a slightly lower yield of decahydroquinoline [2051-28-7]. Catalytic reduction with platinum oxide in strongly acidic solution at ambient temperature and moderate pressure also gives a 70% yield of 5,6,7,8-tetrahydroquinoline [10500-57-9] (33). Further reduction of this material with sodium—ethanol produces 90% of /ra/ j -decahydroquinoline [767-92-0] (34). Reductions of the quinoline heterocycHc ring accompanied by alkylation have been reported (35). Yields vary widely sodium borohydride—acetic acid gives 17% of l,2,3,4-tetrahydro-l-(trifluoromethyl)quinoline [57928-03-7] and 79% of 1,2,3,4-tetrahydro-l-isopropylquinoline [21863-25-2]. This latter compound is obtained in the presence of acetone the use of cyanoborohydride reduces the pyridine ring without alkylation. 

The hydrolysis proceeds via a diazafulvene intermediate, which in these systems can be formed without a total loss of aromatic character of the tricycle. It is tempting to suggest that, using this reasoning, linearly annelated 2-trifluoromethyl-imidazo[4,5-g]quinoline should be inert toward alkaline hydrolysis, as formation of the diazafulvene intermediate will again involve total dearomatization of the heterocyclic system (Scheme 36). 

Amino-6,6n,7,8,910-hexahydropyrido[2,l-c][l,4]benzoxazine was reacted with ethyl 4,4,4-trifluoroacetoacetate in boiling benzene for 12-16 h, then the reaction mixture was concentrated in vacuo and the residue was treated with cone. H2SO4 at 100°C to give tetracyclic 11-trifluoromethyl-l,2,3,4,4a,5,8,9-octahydropyrido[l, 2 4,5][l,4]oxazino[3,2-a]quinolin-9-one in 30% yield (OlMIPl). 

Trifluoromethyl)isoindolinediimine (3.0g. 14.1 mmol) and GcC14 (3.0g, 14.0mmol) were refluxed in quinoline (30 mL) for 4h. After cooling overnight, the precipitate was filtered, washed with HC1, H20, acetone, and McOH. The residue was dried and extracted with benzene to give a blue powder yield 1.88 g (58%). 

Chloro-/3-(trifluoromethyl)acroleins reacted with 2-aminothiophenol at room temperature to give a mixture of a benzothiazole and quinoline. This was in contrast to the /3-methyl analogue, which gave a benzothiazep-ine, the difference being due to the electronic influence of the CF3 group (91TL643). 

Fluorination. Direct fluorination of quinoline was accompanied by extensive fragmentation of the heteroring, but trifluoromethyl hypofluorite in trichlorofluoromethane at -70°C converted 5-fluoro-8-hydroxyquino-line into the 5,7-difluoro-8-hydroxy product (72JMC987). Quinoline, itself, was perfluorinated by fluorine and cobalt(III) fluoride (56JCS783), whereas cesium tetrafluorocobaltate at around 350°C converted it into a mixture of saturated polyfluoro compounds (82JFC413). It is much more satisfactory to introduce fluorine by nucleophilic methods. 

For commonly encountered heterocycles, the chemical shifts of trifluo-romethyl substituents will depend somewhat upon where in the heterocycle they are located. Examples of trifluoromethyl derivatives for a number of common heterocycles, including pyridines, quinolines, pyrroles, indoles, thiophenes, benzothiophenes, furans, benzofurans, imidazoles, and uracils are given below. 

For both pyridines and quinolines, it is easy to distinguish between the 2- and the 4-substituted isomers, since the trifluoromethyl group at the 2-position absorbs at somewhat higher field than that at the 4-position (Scheme 5.45). CF3 at the 3-position appears at a still lower field. 

A series of antimicrobial pyrazolo[3,4-<7]pyrimidines containing 8-(trifluoromethyl)quinoline have been synthesized from 5-amino-1-[8-... 

Under acidic conditions, the formation of a nearly 1 1 mixture of 5- and 7-substituted quinoline-3-carboxylates, with a slight excess of the former, was observed from the 3-chloro- and 3-methyl derivatives. The cycliza-tions of 3-nitro, 3-trifluoromethyl, and methoxy derivatives were carried out only in polyphosphate to give mainly the 7-substituted isomers. 

There have been some further examples of the use of the Conrad-Limpach reaction on substituted 5-aminoquinolines for the synthesis of 4-hydroxy-1,7-phenanthrolines, although the products (see Section IV,F,1) should properly be designated as phenanthrolinones.169 Hot diphenyl ether is often employed as the medium for ring closure.170 Ethyl trifluoro-acetoacetate has been used successfully in place of ethyl aceto-acetate, and this variation has allowed entry to 2-trifluoromethyl-substituted 1,7-phenanthrolines.96 Extensions of the Conrad-Limpach type of synthesis starting with m-phenylenediamine (20) and utilizing diethyl ethoxymethylene malonate or ethyl ethoxalylacetate, reagents frequently used in quinoline syntheses, have afforded, after hydrolysis,... 

When 4-anilino-l,1,1-trifluorobut-3-en-2-ones 17 are heated with phosphorus oxychloride, the resultant 2-(trifluoromethyl)quinolines 18 are the result of a 1,3-vinyl shift from nitrogen to carbon, followed by cyclization and dehydration.18 A wide variety of substitution patterns on the phenyl ring has been investigated. 

Different hydrogenolytic reactivity of trifluoromethyl groups with respect to their position on the quinoline ring is observed. All C-F bonds in 2-, 4- and 6-(trifluoromethyl)quinoline are hydrogenolyzed by lithium aluminum hydride (Table 4), but the 3-trifluoromethyl isomer gave 3-(difluoromethyl)-l,2-dihydroquinoline (10) under the same experimental conditions in contrast to these results, sodium borohydride surprisingly reduces 3-(trifluoromethyl)quinoline to the corresponding 3-methylquinoline (Table 4).149... 

Chloro-2,8-bis(trifluoromethyl)quinoline N,0-Dimethylhydroxylamine hydrochloride Benzyltriethylammonium chloride Sodium hydroxide... 

N-Methoxy-N-methyl-2,8-bis(trifluoromethyl)-quinoline-4-carboxamide was prepared using synthetic methodology reported by Thiesen et al (J. Org. 

To a solution of the N-methoxy-N-methyl-2,8-bis(trifluoromethyl)-quinoline-4-carboxamide amide (10 g, 28.4 mmol) in anhydrous ether (100 ml) was added a solution of 2-pyridyl lithium (Pinder et al (J. Med. Chem. 1968, 11, 267)) [formed by addition of 2-bromopyridine (3.3 ml, 34.6 mmol) to a solution of butyl lithium (29.7 ml of a commercial 1.6 M solution, diluted with an equal quantity of ether) at -78°C] at -78°C. Analysis of the reaction by TLC after 10 min showed that no starting material remained. The reaction was allowed to warm to room temperature, then poured into aqueous ammonium acetate, and extracted with ether, the combined organic layers washed with brine and dried (MgS04). Filtration through a pad of silica gel using ethyl acetate-hexane (1 1) afforded 9.0 g (84%) of the crude 2,8-bis(trifluoromethyl)-4-quinolinyl-2-pyridinylmethanone. This was recrystallised from isopropyl alcohol to give the product as colourless needles, identical to that described in the literature (Hickmann et al. Pinder et al. Ohnmacht et al. and Adam et al. (Tetrahedron 1991, 36, 7609)). 

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